Accumulation of abnormally phosphorylated τ precedes the formation of neurofibrillary tangles in Alzheimer's disease

Bancher, C.; Brunner, Christof; Lassmann, Hans; Budka, Herbert; Jellinger, K. A.; Wiche, Gerhard; Seitelberger, F; Grundke‐Iqbal, Inge; Iqbal, Khalid; Wisniewski, H. M.

doi:10.1016/0006-8993(89)91396-6

Cited by 758 publications

(427 citation statements)

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“…Direct comparison of the experimental 13 C α chemical shifts for wt and E-mutant tau demonstrated that local conformational changes induced by pseudophosphorylation are small and restricted to the vicinity of the mutation. Rigid secondary structure is not induced, in agreement with 3 J HNHA scalar couplings ( Figure S15) and previous work on short tau peptides. 19 Despite the fact that the PHF1 epitope near the C-terminus contains only two phosphorylation sites (396 and 404), 13 C α chemical shift changes were more pronounced and affected a larger set of residues than did glutamic acid mutations in the proline-rich regions, suggesting that the PHF1 epitope is more prone to conformational changes.…”

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confidence: 90%

Structural Impact of Proline-Directed Pseudophosphorylation at AT8, AT100, and PHF1 Epitopes on 441-Residue Tau

et al. 2011

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ABSTRACT:The intrinsically disordered protein tau becomes excessively phosphorylated and aggregates into neurofibrillary tangles in Alzheimer's disease. To obtain insight into the structural consequences of phosphorylation, we characterized a mutant protein of tau in which epitopes recognized by Alzheimer diagnostic antibodies were mimicked by mutation to glutamic acid [AT8 (S199E, S202E, T205E), AT100 (T212E and S214E), and PHF1 (S396E and S404E)]. A large number of distance restraints obtained from NMR paramagnetic relaxation enhancement in combination with ensemble conformer calculations demonstrate that pseudophosphorylation causes an opening of the transient folding of tau. Together with previous studies on the Parkinson-related protein α-synuclein, our data indicate that networks of transient long-range interactions are common properties of intrinsically disordered proteins and that their modulation is important for aggregation.A ggregation of the microtubule-associated protein tau into neurofibrillary tangles is the pathological hallmark of a variety of dementias. 1,2 For reasons not yet known, tau becomes excessively phosphorylated in Alzheimer's brains and as a result no longer binds properly to microtubules. The unbound tau is free to undergo abnormal aggregation. In vivo, hyperphosphorylation of tau precedes tangle formation. 3 At least 30 phosphorylation sites in tau filaments have been identified. 4 Phosphorylation at serine/proline and threonine/proline motifs in the flanking regions of the repeat domain of tau has only a moderate influence on tauÀmicrotubule interactions but is upregulated in Alzheimer's disease. 5 Tau is a prototypical intrinsically disordered protein that does not assume a rigid tertiary or secondary structure but populates an ensemble of interconverting structures in solution. 6,7 Because of the inherent flexibility of tau, NMR spectroscopy is the only method that allows a description of its conformations and dynamics with high resolution. 8 We have recently shown that it is possible to obtain the complete backbone resonance assignment of the longest isoform of human tau and demonstrated that 441-residue tau has a distinct domain character with an intricate network of long-range interactions. 7 Here we investigate changes in the local and global structure of 441-residue tau related to phosphorylation in the epitopes recognized by the Alzheimer diagnostic antibodies AT8 (S199E, S202E, T205E), AT100 (T212E and S214E), and PHF1 (S396E and S404E). To avoid the ambiguities of heterogeneous phosphorylation, we cloned "pseudophosphorylation" mutants of tau in which serine and threonine residues were converted into glutamic acid. The same mutant protein was previously shown to aggregate slightly faster in comparison with wild-type (wt) tau. 9 In addition, a different six-site pseudophosphorylation mutant (S199E, S202E, T205E, T231E, S396E, and S404E) had a decreased rate of elongation and a pronounced lag time of aggregation. 10 We determined cross-validated ensembles of wild-type (wt)...

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confidence: 90%

Structural Impact of Proline-Directed Pseudophosphorylation at AT8, AT100, and PHF1 Epitopes on 441-Residue Tau

et al. 2011

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“…The techniques of Bielschowsky silver impregnation and immunocytochemistry for tau were described in detail earlier [13].…”

Section: Methodsmentioning

confidence: 99%

A high ratio of chromogranin A to synaptin/synaptophysin is a common feature of brains in Alzheimer and Pick disease

et al. 1990

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Chromogranin A and synaptin/synaptophysin were characterized by immunological methods in human autopsy brain tissue from patients with Alzheimer's and Pick's disease. In immunoblots there was no qualitative difference between the antigens in control and diseased brain, but significant quantitative differences were found. In all Alzheimer cases there was a significantly lower level of synaptin/synaptophysin, whereas chromogranin A was higher in 4 out of 5 cases and in all cases relative to synaptin/synaptophysin. An analogous findingwas obtained for Pick's disease. Immunohistologically a consistent staining of neuritic plaques for chromogranin A, but not for secretogranin II was found in Alzheimer cases. In Pick's disease the characteristic Pick bodies showed an analogous specific immunostaining.

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“…16 In AD, the formation of neurofibrillary tangles is preceded by the accumulation of hyperphosphorylated tau. 53 However, although hyperphosphorylation of tau seems to be a prerequisite for tau pathogenesis, 54 it does not necessarily lead to tangle formation, as exemplified by tau hyperphosphorylation during early development. 55 Which form of tau is actually pathogenic is still an ongoing debate.…”

Section: Rmtbi Does Not Induce Amyloid or Tau Pathology In 3xtg-ad Micementioning

confidence: 99%

Dendritic Spine Loss and Chronic White Matter Inflammation in a Mouse Model of Highly Repetitive Head Trauma

Winston

Noël

Neustadtl

et al. 2016

The American Journal of Pathology

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Mild traumatic brain injury (mTBI) is an emerging risk for chronic behavioral, cognitive, and neurodegenerative conditions. Athletes absorb several hundred mTBIs each year; however, rodent models of repeat mTBI (rmTBI) are often limited to impacts in the single digits. Herein, we describe the effects of 30 rmTBIs, examining structural and pathological changes in mice up to 365 days after injury. We found that single mTBI causes a brief loss of consciousness and a transient reduction in dendritic spines, reflecting a loss of excitatory synapses. Single mTBI does not cause axonal injury, neuroinflammation, or cell death in the gray or white matter. Thirty rmTBIs with a 1-day interval between each mTBI do not cause dendritic spine loss; however, when the interinjury interval is increased to 7 days, dendritic spine loss is reinstated. Thirty rmTBIs cause white matter pathology characterized by positive silver and Fluoro-Jade B staining, and microglial proliferation and activation. This pathology continues to develop through 60 days, and is still apparent at 365 days, after injury. However, rmTBIs did not increase b-amyloid levels or tau phosphorylation in the 3xTg-AD mouse model of Alzheimer disease. Our data reveal that single mTBI causes a transient loss of synapses, but that rmTBIs habituate to repetitive injury within a short time period. rmTBI causes the development of progressive white matter pathology that continues for months after the final impact. (Am J Pathol 2016, 186: 552e567; http://dx.doi.org/ 10.1016/j.ajpath.2015 Athletes participating in contact sports are at high risk of exposure to large numbers of concussive and subconcussive mild traumatic brain injuries (mTBIs). Recent studies using head impact telemetry systems have begun to reveal how many head impacts an individual football player can receive in the process of playing his or her sport. In a study of high school football players, the number of helmet impacts >20 g recorded in a single season ranged from a low of 226 (average, 4.7 per session) to a high of 1855 (average, 38.6 per session). 1 Most of these impacts do not result in the clinical diagnosis of a concussion; however, it is not known if the cumulative effects of these impacts can result in increased damage to the brain. mTBI has been extensively modeled in mice and rats. 2 Most of these rodent models use fewer than five mTBIs, and report adverse events, including intracerebral bleeding, skull fractures, severe axonal injury, neuronal cell death, and increased mortality.

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Accumulation of abnormally phosphorylated τ precedes the formation of neurofibrillary tangles in Alzheimer's disease

Cited by 758 publications

References 20 publications

Structural Impact of Proline-Directed Pseudophosphorylation at AT8, AT100, and PHF1 Epitopes on 441-Residue Tau

Structural Impact of Proline-Directed Pseudophosphorylation at AT8, AT100, and PHF1 Epitopes on 441-Residue Tau

A high ratio of chromogranin A to synaptin/synaptophysin is a common feature of brains in Alzheimer and Pick disease

Dendritic Spine Loss and Chronic White Matter Inflammation in a Mouse Model of Highly Repetitive Head Trauma

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